Coronary artery disease (CAD) is a worldwide leading cause of heart attacks, death and disability, and leads to billions of dollars of healthcar expenditures each year. Clinically, a widely effective interventional treatment for CAD is percutaneous coronary intervention (PCI) using coronary metal stents. Over 1 million coronary stents are placed annually in the US alone. Yet, two complications can limit the benefit of coronary stents: restenosis (scarring), and thrombosis (clotting). Prevention of plaque progression and stent complications would eliminate hundreds of thousands of invasive catheterizations, heart attacks, and deaths each year. Biologically, inflammation underlies all of these diseases: atherosclerosis, stent restenosis, and stent thrombosis. Yet the in vivo mechanisms by which inflammation drives plaques progression and the injury response to stenting remains poorly understood. The ability to quantitatively image inflammation in vivo, especially with translatable technology, could provide clinically relevant, vital new insights into these disorders. To address this unmet need, our laboratory is developing coronary artery-targeted intravascular near-infrared fluorescence (NIRF) molecular imaging approaches to image and quantify arterial inflammation and stent healing. Most recently we have developed an early-stage intravascular NIRF-optical frequency domain imaging (OFDI, Nature Medicine 2011; 17:1680-4) system to quantitatively image molecular signals in the context of arterial structure. The objective of this Proposal is to develop translatable intravascular NIRF-OFDI molecular-microstructural imaging approaches to better understand mechanisms of plaque progression and stent complications. This Proposal tests the central hypothesis that integrated NIRF-OFDI will comprehensively assess the role of in vivo inflammation in driving plaque progression, stent restenosis, and stent thrombosis. Our long-term goal is to assess inflammatory mechanisms in human coronary arteries and to ultimately reduce the immense burden of CAD and stent complications. The Specific Aims of this proposal are: Specific Aim 1. To engineer a next-generation intravascular NIRF-OFDI 2.9F catheter system. Specific Aim 2. To determine how plaque inflammation modulates atheroma progression and stent restenosis. Specific Aim 3. To determine how plaque inflammation modulates stent healing and risk of stent thrombosis. This research will transform the field of atherosclerosis and coronary stenting by (1) providing new, valuable pathobiological knowledge about the role of inflammation in regulating atheroma progression, restenosis, and stent malhealing; and (2) provide translatable strategies for inflammation-structural imaging, to ultimately improve the outcomes of patients with CAD and those undergoing coronary stenting.